Dysfunctional Orexin-Regulated Neural Circuits in Alzheimer's Disease

阿尔茨海默病中食欲素调节的神经回路功能失调

• 批准号: 10372270
• 负责人: Paulette B. Goforth
• 金额: $ 15.6万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372270
• 关键词: Affect; Age; Age-Months; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Area; Arousal; Autopsy; Calcium; Cell physiology; Cerebrospinal Fluid; Cognitive deficits; Data; Defect; Development; Disease; Disorientation; Down-Regulation; Electrophysiology (science); Exhibits; Follow-Up Studies; Functional disorder; Health; Image; Impaired cognition; Impairment; Infusion procedures; Knowledge; Lead; Lesion; Mediating; Memory; Memory impairment; Molecular; Mus; Neuronal Dysfunction; Neurons; Neuropeptides; Pathway interactions; Periodicity; Persons; Physiological; Physiological Processes; Population; Preparation; Process; Regulation; Rodent Model; Role; Shapes; Signal Transduction; Slice; Spatial Behavior; Symptoms; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Work; antagonist; base; experience; human model; hypocretin; improved; in vivo; mouse model; network dysfunction; neural circuit; novel; optogenetics; orexin 1 receptor; preservation; prevent; receptor; relating to nervous system; repaired; response; spatial memory; targeted treatment; therapeutic target; way finding

Persons with Alzheimer's Disease (AD) experience spatial disorientation that emerges early in the disease process. In both humans and rodent models of AD, dysfunction within the retrosplenial cortex (RSC), a crucial locus for spatial navigation and memory, is observed prior to the onset of cognitive decline. Understanding the mechanisms underlying RSC dysfunction is important to develop strategies aimed at improving spatial navigation and memory in AD. We observe aberrant RSC network activity that includes reduced RSC rhythmic synchrony during spatial navigation in a mouse model of AD, yet the cellular and molecular basis for these defects are unknown. Here, using a newly developed mouse line, we identify a specific population of RSC neurons that express the orexin 1 receptor (RSCOX1R) and are activated by the neuropeptide orexin. In WT mice, direct stimulation of these RSCOX1R neurons enhances RSC synchrony, suggesting these neurons are an important population in which to examine cellular mechanisms of AD-related RSC dysfunction, and to target for therapeutic intervention. Orexin signaling affects numerous physiologic processes, including spatial memory, and abnormalities in orexin signaling are implicated in AD pathology. Studies of specific orexin-regulated memory circuits in AD is lacking, however. In this proposal, we examine whether RSCOX1R neurons are directly altered in the 5xFAD model of AD (Aim 1). We also test the hypothesis that the activation of RSCOX1R neurons or enhancement of orexin-signaling/regulation of RSC neurons can restore the AD-associated deficits in RSC rhythmic activity (Aim 2). The completion of this work will pave the way for larger-scale follow up studies across multiple models of AD, with the potential to identify novel RSC and orexin-based therapies aimed at ameliorating a range of spatial memory and cognitive deficits in persons with AD.

阿尔茨海默氏病（AD）经历了这种疾病早期出现的空间迷失方向的人 过程。在人类和AD的啮齿动物模型中，肾上腺皮质（RSC）内的功能障碍，至关重要 在认知下降开始之前，观察到用于空间导航和记忆的基因座。了解 RSC功能障碍的基础机制对于制定旨在改善空间的策略很重要 广告中的导航和内存。我们观察到异常的RSC网络活动，包括减少RSC节奏 在AD小鼠模型中空间导航期间的同步，但这些细胞和分子基础这些基础 缺陷未知。在这里，使用新开发的鼠标线，我们确定了RSC的特定群体 表达Orexin 1受体（RSCOX1R）并被神经肽Orexin激活的神经元。在wt 小鼠，直接刺激这些RSCOX1R神经元增强了RSC同步，这表明这些神经元是一种 重要人群检查与AD相关RSC功能障碍的细胞机制，并针对 治疗干预。 Orexin信号传导影响许多生理过程，包括空间记忆， Orexin信号传导中的异常与AD病理有关。特定OREXIN调控的研究 但是，缺乏广告中的内存电路。在此提案中，我们检查了RSCOX1R神经元是否直接 在AD的5XFAD模型中改变（AIM 1）。我们还测试了RSCOX1R神经元激活的假设 或增强RSC神经元的Orexin-Signaling/调控可以恢复RSC中与AD相关的缺陷 节奏活动（目标2）。这项工作的完成将为大规模的后续研究铺平道路 AD的多种模型，有可能识别针对的新型RSC和基于Orexin的疗法 改善AD人的一系列空间记忆和认知缺陷。